Expert Reflects on Recent Pivotal Data in RCC

Daniel J. George, MD

Renal cell carcinoma (RCC) is a field that is shifting dramatically in the metastatic setting, but progress has been slower for patients with high-risk stage III disease, said Daniel J. George, MD.

The future of treatment for patients with stage III disease should be individualized, he said, and with the newly available data, physicians should have an open line of communication with their patients about treatment options.

OncLive^®: What are the recent data seen with TKIs in the landscape?

In an interview with OncLive^® during the 2018 State of the Science Summit^TM on Genitourinary Cancers, George, professor of Medicine and Surgery, member, Duke Cancer Institute, discussed the status of treatment for patients with high-risk stage III RCC, as well as the role of sunitinib (Sutent) and checkpoint inhibitors in the RCC paradigm.George: RCC is a field that is dramatically changing—we are making progress in advanced metastatic disease. However, for patients with stage III disease who are high risk for disease recurrence after surgery, there really have not been any breakthroughs until recently. For the most part, that has been an unmet need. We have done some clinical trials looking at TKIs in that setting.

One study was positive. That was the S-TRAC study, which looked at the use of sunitinib (Sutent) for 1 year versus placebo in patients with high-risk disease. In that patient population, we demonstrated a 24% reduction in risk of disease recurrence for the entire population. At 5 years, there was an absolute improvement in recurrence-free survival of 8%, roughly 1 out of 12. Overall, there was an approximate 50% disease recurrence for that population at 5 years, so this was indeed a high-risk patient population.

This was a positive study that led to an FDA approval. It is interesting to us that in this context, there has not been a lot of use of sunitinib in this setting, and there has been some pushback regarding the results because of some other studies that were contemporary and did not meet their primary endpoints.

The ASSURE study was one of those studies. This looked at sunitinib, sorafenib (Nexavar), and placebo, demonstrating no difference in disease-free survival (DFS). But, there were a lot of dose reductions all the way down to 25 mg of sunitinib. About two-thirds of the way through, they changed the dosing from 50 mg down to 37.5 mg. That relative decrease probably explains a lot of why we did not see the efficacy.

In the PROTECT study of pazopanib (Votrient), a similar drug to sunitinib, they changed the initial dose from 800 mg to 600 mg halfway through due to tolerance. What we found was that in the patients who started at 800 mg, there was indeed a statically significant improvement in DFS similar to what was seen in S-TRAC. However, in the patients who had the dose reduction from the beginning, there was a reduction of that effect that was no longer statistically significant.

Could you expand on the evolution of sunitinib’s role over the last few years?

Therefore, dose matters when it comes to the adjuvant setting. The struggle is that dose also results in toxicity. How to balance that is key. Identifying patients who have fully recovered with [an ECOG performance status of] 0 following surgery is important, and counseling patients around the tolerance and being proactive with dose interruptions, rather that dose reductions, is very important. However, if you do that, there is definitely a patient population out there that can benefit and tolerate these drugs in this setting.Sunitinib has been in the field for over 10 years. It was approved by the FDA in 2006 based on some robust progression-free survival (PFS) data versus interferon in frontline metastatic RCC. It has been the mainstay of our treatment for metastatic RCC since then. However, in the last couple of years, we have begun to see trials reporting out comparing other agents with sunitinib, particularly in patients with intermediate- and poor-risk disease. In those settings, nivolumab (Opdivo) and ipilimumab (Yervoy) showed a statistically significant improvement in overall survival in those patients treated with immunotherapy versus sunitinib.

How would you say that immunotherapies are impacting the role of TKIs?

In the CABOSUN study, they looked at cabozantinib (Cabometyx) versus sunitinib and saw a PFS benefit in favorite of cabozantinib versus sunitinib in that intermediate- to poor-risk population. It looks like there may be other treatment options that are preferable for these patients with intermediate and poor-risk clinical features. For patients with good-risk clinical features, sunitinib is still a frontline treatment option. I believe that immunotherapies are a tremendous compliment to the field. Unfortunately, most of our patients treated with immunotherapy eventually progress. We are using TKIs following immunotherapy, and we are seeing success with that as well. That includes agents such as pazopanib, cabozantinib, axitinib (Inlyta), lenvatinib (Lenvima), and everolimus (Afinitor). There are still a lot of treatment options with TKIs for these patients. Using immunotherapy in the frontline setting for intermediate- and high-risk disease makes a lot of sense.

What are the concerns with immune-related adverse events with immunotherapy?

For good-risk disease, we are still in a monotherapy, sequential approach. There, immunotherapy hasn't necessarily demonstrated a superiority over sunitinib. VEGF TKIs are still our frontline treatment option in that setting. What is exciting now is the combination of immunotherapy with VEGF TKIs. We want to see that data mature a little bit more before we fully pass judgement, but the results we have seen from the JAVELIN 101 study, and what we hope to see from the pembrolizumab (Keytruda)/axitinib study, will tell us if there is a role for combining these agents in the frontline setting. Anytime we use immunotherapy, there is a risk for side effects. The thing about immunotherapy is that they tend to stay in the body a long time. When we do get toxicities, they can be slow to recover, such as rashes, pneumonitis, and colitis. Thankfully, those are relatively rare, but when we do see those, we are using steroids, sometimes prolonged courses. For the most part, we will not start our next-line therapy until see a resolution of those, at least down to grade 1 or less. We have seen significant delays. In my experience, that hasn't necessarily resulted in disease progression. While we are getting those toxicities, we may still be getting some treatment effect associated with immunotherapy.

How do you approach sequencing for patients in each risk group?

For me, it has not been a deterrent for the majority of our patients, but it does require management and proactive management to prevent these very high-grade complications from happening. When I look at these risk groups, I tend to look at good-risk patients as patients who will live a long time. That is based on their risk group stratification and their tumor burden. There is also a role for active surveillance in many of these good-risk, low-volume patients.

Intermediate risk is probably our biggest risk group overall. It is about 60% of our population, so it is where a lot of our patients fall. This is where I like to be proactive, because these are patients who are a little bit unpredictable. In general, I treat these patients with an immunotherapy-based regimen.

For patients with poor-risk disease, it really depends on what patients can tolerate. For many of them, patients may need immediate palliation, and drugs such as cabozantinib can result in very quick responses, which can be helpful. We can then transition to other agents later on. Some of these patients just need palliation and good supportive care, because the disease can be overwhelming.

Is there anything else you would like to emphasize about your approach to treatment?

What would you like seen addressed in the next few years?

It is a challenging spectrum; we do have to individualize. Also, I think about tumor burden and symptoms in that context. The most important thing to recognize is that there are treatment options for patients with stage III disease. Ask your patients. Your patients deserve the right to hear about these options. Whether it be clinical trials, targeted therapies with TKIs, or observation. It is the right of our patients to know all their options. As treating physicians, it is our obligation to present that in a balanced way so that they can make the most informed decision. In the next 5 years or so, I'd like to see us cure more patients. Curing more patients means treating patients in the adjuvant setting, but also recognizing the curative approaches to oligometastatic disease, and how can we incorporate our definitive treatments and immunotherapy there. For our patients with intermediate- and high-risk disease, how can we get to complete response? How can we layer on therapies sequentially before disease progression? These are important questions.

We have to find how to treat nonclear cell cancers better. We are going to need to understand when MET is the standard for papillary cancers, and if it is, how do we put immunotherapy into that. What are we missing? What is different about clear cell besides MET? A lot of work has to be done. There are other immunologic targets in RCC that I would like to see move into these frontline spaces quickly; that is where we are going to see the greatest effects.